Who should be tested for hereditary haemochromatosis?

Testing is recommended for anyone with a known first-degree relative who has confirmed hereditary haemochromatosis, and for people whose blood tests happen to show a raised transferrin saturation (above 45%) or an unexplained elevated ferritin. Symptoms that should prompt testing include unexplained fatigue, joint pain in the second and third knuckle joints, new diabetes with skin discolouration, reduced libido or erectile dysfunction, or abnormal liver function tests. Because hereditary haemochromatosis is common in people of Northern-European — particularly Irish, Scottish, and Welsh — descent, ancestry is a useful piece of context when deciding whether to investigate.

What does a fasting transferrin saturation above 45% mean?

Transferrin saturation measures what proportion of the iron-carrying protein in your blood (transferrin) is actually loaded with iron. A fasting result above 45% means the body is absorbing iron faster than it can safely handle — iron starts to overflow and deposit in organs including the liver, pancreas, heart, and joints. By itself it does not confirm hereditary haemochromatosis; it is the trigger for the next step, which is HFE gene testing. The sample must be fasting because eating, particularly an iron-containing meal or vitamin C supplement, can transiently push the result above 45% in someone without haemochromatosis.

How does therapeutic venesection work and how often is it needed?

Therapeutic venesection — essentially a blood donation — removes 450 to 500 mL of blood, which carries away roughly 200 to 250 mg of iron. During the initial treatment phase, sessions are usually weekly or fortnightly until the ferritin level falls into the target range of 50 to 100 micrograms per litre. Depending on how much iron has accumulated, induction can take months to a couple of years. Once the target is reached, maintenance sessions — typically every two to four months — keep the ferritin in a safe range lifelong. Through the Australian Red Cross Lifeblood therapeutic donation programme, eligible patients can have their blood used for transfusion at no cost.

Can the complications of haemochromatosis be reversed once iron is removed?

Liver fibrosis that has not yet progressed to full cirrhosis can improve substantially once iron stores are depleted — this is one of the strongest arguments for early detection and treatment. Early-stage heart muscle changes related to iron loading can also recover. Joint damage, pancreatic islet cell injury causing diabetes, and hypogonadism caused by iron-loaded pituitary or testicular tissue are unfortunately largely irreversible — the damage to these structures does not undo itself with iron removal. This is why it matters enormously to find hereditary haemochromatosis before symptoms of organ injury develop, which is exactly the goal of family cascade testing.

What foods and supplements should I avoid if I have haemochromatosis?

The single most important dietary warning is raw shellfish — oysters, mussels, and other raw seafood carry the bacterium Vibrio vulnificus, which thrives in iron-rich environments and can cause a rapidly fatal blood infection in people with iron overload. Mortality from Vibrio vulnificus in haemochromatosis exceeds 50%. Cooked seafood is safe. Iron supplements — including many men's and energy multivitamins — must be avoided because they directly add to iron stores. High-dose vitamin C supplements above 200 to 250 mg per day should be limited, as ascorbic acid enhances iron absorption and can mobilise stored iron. Alcohol should be restricted and avoided entirely in anyone with elevated ferritin or liver disease, as it greatly worsens the liver injury that iron causes.

What does cascade testing mean for my family and what will they be told?

Cascade testing means offering iron studies and HFE gene testing to every adult first-degree relative — parents, siblings, and adult children — of someone diagnosed with hereditary haemochromatosis. Because the condition is autosomal recessive, each sibling of a C282Y homozygote has a one in four chance of also carrying two copies of the gene change. Finding the condition in a relative before they develop symptoms means treatment can begin early and complications can be prevented. Before HFE genotyping is arranged, your GP will discuss what a positive result might mean for life insurance applications, because under current Australian legislation, insurers may in some circumstances ask about genetic test results.

Hereditary haemochromatosis

Hereditary haemochromatosis: diagnosis, venesection, and cascade testing

By Dr HB Lo, FACRRM Reviewed 20 June 2026 12 min read

Hereditary haemochromatosis (HH) — the most common autosomal-recessive disorder in Northern-European populations — affects about one in 200 Australians, the highest HFE C282Y prevalence globally.

Diagnosis starts with a fasting transferrin saturation above 45% and elevated ferritin, confirmed by HFE genotyping. Treatment is lifelong therapeutic venesection; the Lifeblood therapeutic donation programme is the preferred Australian pathway.

Complications — cirrhosis, liver cancer, diabetes, hypogonadism, and arthropathy — are largely preventable when treated before end-organ damage. All adult first-degree relatives need cascade testing.

Australia carries the world’s highest burden of hereditary haemochromatosis

Hereditary haemochromatosis (HH) is the most common serious autosomal-recessive disorder in Australians of Northern-European descent. The HFE C282Y variant — the mutation responsible for more than 90% of cases — reached its current extraordinary frequency through a founder effect in Celtic and Norse populations. The result is that roughly one in 150 to 200 Australians carries two copies of C282Y, giving this country the highest documented population prevalence of the genotype in the world, per Pietrangelo (NEJM 2010) and Haemochromatosis Australia.

The condition is important in general practice because it is treatable — often completely preventable in terms of complications — yet up to 40% of affected Australians remain undiagnosed until iron has already accumulated enough to injure the liver, joints, pancreas, or heart. The treatment is straightforward: periodic removal of blood. Complications that develop before treatment begins, however, may be permanent.

eTG complete and the RACGP genomics framework are the primary Australian reference documents; clinical guideline recommendations are provided by AASLD 2011 (Bacon), EASL 2010, and the recent BSG 2024 (Fitzsimons).

A. Core clinical — the AU general-practice framework

Who develops iron-overload disease?

Penetrance is strikingly incomplete. The landmark Melbourne Collaborative Cohort analysis (Allen NEJM 2008) followed C282Y homozygotes through middle age and found iron-overload-related clinical disease in only 28% of men and 1% of women — far fewer than historical case series suggested. Biochemical penetrance (a raised transferrin saturation or ferritin) is higher than clinical penetrance. The implication is that not every genotype-positive individual will develop organ damage, but those who do can develop it silently.

Key modifiers of clinical expression include:

Sex — menstruation and pregnancy protect women against iron accumulation; female C282Y homozygotes typically declare disease one to two decades later than men, often after menopause
Alcohol use — the most potent modifiable co-factor; alcohol and iron are synergistically hepatotoxic
Obesity and metabolic steatotic liver disease (MASLD) — accelerates fibrosis at any given ferritin
Viral hepatitis B or C — additive liver injury
Compound heterozygosity (C282Y / H63D) — usually modest iron loading; requires a co-factor to become clinically significant

Recognising the clinical presentation

Symptoms are non-specific early and often appear in the fourth to sixth decade in men:

Fatigue and lethargy — the most common presenting complaint, frequently attributed to other causes
Joint pain — classically affecting the second and third metacarpophalangeal (MCP) joints (“iron fist”), plus wrists, hips, and knees; chondrocalcinosis and pseudogout flares
Sexual dysfunction — reduced libido, erectile dysfunction, testicular atrophy, secondary amenorrhoea (iron-loaded pituitary reduces LH/FSH secretion causing hypogonadotrophic hypogonadism)
New-onset diabetes — pancreatic islet cell iron loading
Skin discolouration — slate-grey or bronze hyperpigmentation, particularly on sun-exposed areas, axillae, and groin; the classic late triad of cirrhosis + diabetes + bronze skin is now rarely seen at first presentation in Australia
Cardiac symptoms — breathlessness, palpitations, or signs of restrictive or dilated cardiomyopathy

On examination: slate-grey pigmentation, hepatomegaly, 2nd/3rd MCP joint swelling or squaring, small testes, loss of body hair, and stigmata of chronic liver disease if advanced.

Investigation pathway

Step 1 — Fasting iron studies (Bacon AASLD 2011; BSG 2024):

Transferrin saturation (TSAT) >45% is the primary screening abnormality — sensitivity ~94% for HFE-HH. The sample must be fasting; recent iron supplements or vitamin C can transiently elevate TSAT.
Serum ferritin — elevated in iron loading, but also raised by alcohol, MASLD, viral illness, and inflammation. Always interpret alongside CRP and TSAT. Thresholds for iron-overload concern: >200 µg/L in men, >150 µg/L in premenopausal women, >300 µg/L in postmenopausal women. Ferritin >1000 µg/L indicates serious tissue loading and a high probability of significant fibrosis.
LFTs, FBC, HbA1c, fasting glucose, testosterone (men), CRP complete the initial work-up.

Step 2 — HFE genotyping when TSAT >45% and ferritin is elevated (or first-degree family history):

Confirms biallelic p.Cys282Tyr (C282Y) or compound C282Y / H63D status. Under the RACGP genomics framework, pretest counselling and written informed consent are required before genotyping — the result has implications for life insurance under current Australian legislation (see section C).

Step 3 — Stage end-organ disease once diagnosis is confirmed:

Transient elastography (FibroScan) — liver stiffness below 7 kPa excludes advanced fibrosis; ≥13 kPa suggests cirrhosis in HH (BSG 2024)
Hepatic MRI T2*/R2 — gold-standard non-invasive liver iron quantification; available in most Australian tertiary centres
Liver biopsy — now reserved for ferritin >1000 µg/L with abnormal LFTs or hepatomegaly where elastography is inconclusive, or when non-HFE iron overload is suspected

Critical pitfall: isolated hyperferritinaemia with a normal TSAT is not HH — redirect work-up toward MASLD, alcohol-related liver disease, or chronic inflammation rather than ordering HFE genotyping.

Treatment — therapeutic venesection

Venesection is simple, inexpensive, safe, and effective. Each session removes 450–500 mL of blood, carrying away 200–250 mg of iron — roughly the amount a non-haemochromatotic adult absorbs from diet over one to three months.

Induction phase (Adams Hepatology 2016; BSG 2024):

Weekly or fortnightly sessions until ferritin falls to 50–100 µg/L and TSAT is below 50%
Check Hb before each session (defer if Hb is below 120 g/L)
Monitor ferritin every two to four weeks during induction; each 1 g/L of removed haemoglobin removes roughly 3 mg of iron

Maintenance phase (lifelong):

One unit every two to four months; individualised to keep ferritin in the 50–300 µg/L range
Some postmenopausal women need only one to two sessions per year
Avoid ferritin falling below 50 µg/L — avoid inducing iron deficiency

Australian Red Cross Lifeblood therapeutic donation is the preferred pathway in eligible patients (Lifeblood; Haemochromatosis Australia). Blood donated by patients who meet donor eligibility criteria (Hb ≥120 g/L, no high-risk behaviours or recent travel disqualifiers) is used for transfusion — a socially meaningful and cost-free pathway. Patients ineligible for donation (e.g. recent travel to malaria-endemic areas, certain medications) need hospital outpatient or private venesection, billed under MBS items 13757 (initial) and 13754 (subsequent).

Chelation therapy — deferasirox (Exjade / Jadenu) or deferoxamine — is reserved for the rare patient who cannot tolerate venesection due to severe anaemia, decompensated heart failure, or no venous access. Deferasirox is not PBS-funded for HFE-HH and is generally prescribed via special access; specialist supervision is required.

Monitoring and follow-up cadence

Induction: ferritin + TSAT every two to four weeks; FBC (Hb) before each session
Maintenance: ferritin + TSAT every three to six months; LFTs, HbA1c, and testosterone (if previously low) annually
Fibrosis re-assessment: FibroScan every one to three years in patients with F0–F2 at diagnosis; specialist-led if cirrhotic
HCC surveillance: 6-monthly liver ultrasound ± AFP for cirrhotic patients only (EASL 2022) — non-cirrhotic HH patients do not require routine HCC surveillance

B. Evidence base — key studies

Allen et al. (NEJM 2008) — The Melbourne Collaborative Cohort and HealthIron study followed 1084 C282Y homozygotes and found iron-overload-related disease in 28.4% of men and 1.2% of women. This landmark paper redefined the penetrance of HFE-HH and is the key reference when counselling patients that a positive genotype is not a sentence to serious disease.

Adams et al. — HEIRS Study (NEJM 2005) — This North American screening study of over 100,000 participants confirmed C282Y homozygote frequency across ethnic groups and contributed the key biochemical penetrance data (TSAT and ferritin elevation rates in C282Y homozygotes) that underpin current screening thresholds.

Adams et al. (Hepatology 2016) — This clinical guidance paper from AASLD formulated the induction target of ferritin 50–100 µg/L and the maintenance range of 50–300 µg/L, providing the quantitative framework that current guidelines adopt.

BSG 2024 (Fitzsimons, Gut) — The most current major guideline reaffirms TSAT-first screening, HFE genotype confirmation, ferritin 50–100 µg/L induction target, and venesection via therapeutic donation as the preferred pathway. It updates fibrosis assessment to favour transient elastography over biopsy in most cases.

USPSTF 2006 — Recommendation statement found insufficient evidence to recommend general population screening for HFE-HH, citing incomplete penetrance as the key concern. The conclusion — case-finding in symptomatic or family-history patients, plus cascade testing of first-degree relatives — remains the international consensus.

EASL 2022 (HCC guidelines) — Explicit guidance that HCC surveillance (6-monthly ultrasound ± AFP) is indicated for cirrhotic HFE-HH but is not standard practice in non-cirrhotic patients, resolving a common point of confusion in practice.

C. Australian operations

MBS items

GP consultations: items 23 / 36 / 44; telehealth video 91790 and phone 91891 (existing-relationship rule)
GPCCMP chronic-condition management: item 965 preparation and 967 review (replaced GPMP/TCA 1 July 2025) — applicable when HH has produced end-organ disease (cirrhosis, diabetes, hypogonadism, cardiomyopathy, arthropathy) requiring multi-disciplinary care
Pathology — iron studies: ferritin item 66596; LFTs 66512; HbA1c 66551; testosterone 66536
HFE genotyping — funded under the MBS pathology genetics bundle (items 73317/73329 family) in patients with appropriate phenotype or confirmed family history. Pretest counselling and written consent required
Liver ultrasound 55054 — 6-monthly for cirrhotic HCC surveillance; initial staging
Therapeutic venesection: 13757 (initial with management), 13754 (subsequent) — for hospital outpatient or private clinic venesection where Lifeblood is not available or patient is ineligible
DEXA 12306 — for hypogonadism or ferritin >1000 µg/L with osteoporosis risk factors
Hepatology referral: consultant physician attendance 132 initial / 133 subsequent

PBS prescribing

Iron supplements (ferrous sulfate, fumarate, gluconate) — PBS-listed but absolutely contraindicated in HH — do not prescribe
Deferasirox (Exjade / Jadenu) — PBS Authority Required, restricted to transfusional iron overload (thalassaemia, MDS, sickle cell); not PBS-funded for HFE-HH; private script or special access if venesection is contraindicated
Testosterone (PBS Authority Required) — for documented hypogonadism after iron depletion; start testosterone only once iron stores are adequately depleted, as early testosterone can worsen erythropoiesis and iron loading
Vitamin C high-dose preparations — over-the-counter; counsel against >200–250 mg daily

Genomic counselling and insurance implications

Under current Australian legislation, life insurers may request genetic test results in some circumstances. Before arranging HFE genotyping, the GP should discuss this with the patient and document the conversation per the RACGP genomics framework. Patients considering large life, total permanent disability, or income protection insurance applications should be counselled about timing before testing. The moratorium framework is evolving — check current RACGP guidance for the most recent position.

Key Australian resources

Haemochromatosis Australia — peer support, cascade testing navigator, Lifeblood enrolment pathway
Australian Red Cross Lifeblood — Therapeutic venesection — enrolment for therapeutic donation
GESA — hepatology / gastroenterology specialist referral and position statements
HealthDirect — Haemochromatosis — consumer information

D. Lifestyle and dietary management

Beyond venesection, these measures reduce co-factor load and the risk of complications:

Alcohol restriction — limit to ≤2 standard drinks per day per NHMRC; abstain entirely if ferritin >1000 µg/L, cirrhotic, or symptomatic liver disease. Alcohol is the most powerful modifiable driver of fibrosis in iron-loaded livers
No iron supplements — including iron-containing multivitamins; read product labels carefully. Many “men’s” and “energy” vitamin formulations contain iron
Limit vitamin C to ≤200–250 mg per day from supplements; food-source vitamin C (vegetables, fruit) is not a concern at normal dietary quantities
No raw shellfish, ever — oysters, mussels, and other raw seafood carry Vibrio vulnificus, a bacterium that multiplies explosively in iron-rich environments. Mortality from Vibrio vulnificus septicaemia in iron-overloaded patients exceeds 50%. Fully cooked seafood is safe
Avoid raw and undercooked meats — Listeria and Yersinia (organisms with a preference for iron-rich hosts)
Diet does not need to be iron-restricted — venesection is so effective that avoiding red meat adds minimal benefit and reduces quality of life; common-sense moderation is reasonable
Tea or coffee with iron-containing meals — tannins and polyphenols modestly reduce non-haem iron absorption; a low-effort adjunct
Weight management and exercise — 150 minutes per week moderate aerobic activity plus resistance training; reduces MASLD co-factor burden and preserves bone and muscle mass in hypogonadal men
Vaccination — hepatitis A and B (if non-immune), annual influenza, and COVID boosters are especially important for patients with significant iron loading or cirrhosis
Avoid high-dose curcumin / turmeric supplements — culinary turmeric is fine; concentrated curcumin-piperine capsules have been associated with hepatotoxicity in vulnerable livers

E. Special populations

Women — female C282Y homozygotes have very low clinical penetrance (1% in Allen NEJM 2008) through reproductive years due to iron loss through menstruation and pregnancy. After menopause, iron accumulates and ferritin can rise rapidly. Annual monitoring with ferritin and TSAT from the perimenopausal years is appropriate in known C282Y homozygotes. Pregnancy in a woman with HH does not require alteration of the monitoring schedule — iron levels typically fall further, and venesection is generally paused.

Compound heterozygotes (C282Y/H63D) — most do not develop clinically significant iron overload without a co-factor. If ferritin and TSAT are elevated in a C282Y/H63D individual, look carefully for alcohol use, MASLD, or viral hepatitis as the primary driver before attributing overload to the HFE genotype alone.

Non-HFE iron overload — juvenile haemochromatosis (hemojuvelin or HAMP mutations) presents under age 30 with severe cardiac and gonadal failure. Ferroportin disease (SLC40A1) is autosomal dominant and paradoxically presents with very high ferritin but normal or low TSAT due to reticuloendothelial iron trapping — these patients may not tolerate aggressive venesection and need specialist guidance. Any patient with phenotypic iron overload and a negative or non-classic HFE result should be referred to hepatology for expanded genetic and liver assessment.

Aboriginal and Torres Strait Islander patients — C282Y allele frequency is very low in non-admixed Aboriginal and Torres Strait Islander populations. Iron overload in this group is far more likely to be secondary — related to chronic transfusion, alcohol-related liver disease, chronic inflammation, or ineffective erythropoiesis — than hereditary. HFE genotyping is rarely the appropriate first test without European admixture in the family history.

Cirrhotic HH — once cirrhosis has developed, the standard hepatocellular carcinoma (HCC) risk remains even after iron is fully depleted. Six-monthly liver ultrasound with or without AFP is mandatory for life, regardless of ferritin normalisation. Decompensation (ascites, variceal haemorrhage, encephalopathy, jaundice) requires immediate hepatology referral and consideration of liver transplant assessment.

When to escalate

Emergency (000):

Jaundice with confusion or encephalopathy (decompensated cirrhosis)
Haematemesis or melaena (variceal or peptic haemorrhage)
Sudden severe breathlessness or cardiac arrhythmia (iron-loaded cardiomyopathy)
Fever and rapid deterioration after eating raw shellfish (Vibrio vulnificus septicaemia — immediate life-threatening emergency)
New ascites developing over hours to days

Same-day hepatology / gastroenterology assessment:

Ferritin >1000 µg/L with abnormal LFTs or thrombocytopenia (high probability of cirrhosis)
New hepatic lesion on ultrasound (possible HCC)
Clinical jaundice without encephalopathy
New peripheral oedema, ascites, or abdominal discomfort in a known HH patient

Routine hepatology referral:

All newly diagnosed HH for fibrosis staging (FibroScan ± liver biopsy if ferritin >1000 µg/L) and to establish a shared-care plan
Phenotypic iron overload with negative or non-classic HFE genotype (non-HFE work-up)
End-organ disease needing specialist co-management (endocrinology for hypogonadism/diabetes, cardiology for cardiomyopathy, rheumatology for severe arthropathy)

What this article is and is not

This is general health information drawn from eTG complete, the RACGP genomics framework, AASLD 2011 (Bacon), EASL 2010, BSG 2024 (Fitzsimons), Adams Hepatology 2016, and the population data from Allen NEJM 2008 and Adams HEIRS NEJM 2005. It is not personal medical advice and does not create a doctor–patient relationship. Decisions about iron study interpretation, venesection frequency, cascade testing, and referral are made by the treating GP and specialist team who know the individual clinical picture.

For consumer information: Haemochromatosis Australia, Lifeblood — Therapeutic venesection, HealthDirect — Haemochromatosis, Better Health Channel.

Sources cited

Frequently asked questions

Who should be tested for hereditary haemochromatosis?

Testing is recommended for anyone with a known first-degree relative who has confirmed hereditary haemochromatosis, and for people whose blood tests happen to show a raised transferrin saturation (above 45%) or an unexplained elevated ferritin. Symptoms that should prompt testing include unexplained fatigue, joint pain in the second and third knuckle joints, new diabetes with skin discolouration, reduced libido or erectile dysfunction, or abnormal liver function tests. Because hereditary haemochromatosis is common in people of Northern-European — particularly Irish, Scottish, and Welsh — descent, ancestry is a useful piece of context when deciding whether to investigate.
What does a fasting transferrin saturation above 45% mean?

Transferrin saturation measures what proportion of the iron-carrying protein in your blood (transferrin) is actually loaded with iron. A fasting result above 45% means the body is absorbing iron faster than it can safely handle — iron starts to overflow and deposit in organs including the liver, pancreas, heart, and joints. By itself it does not confirm hereditary haemochromatosis; it is the trigger for the next step, which is HFE gene testing. The sample must be fasting because eating, particularly an iron-containing meal or vitamin C supplement, can transiently push the result above 45% in someone without haemochromatosis.
How does therapeutic venesection work and how often is it needed?

Therapeutic venesection — essentially a blood donation — removes 450 to 500 mL of blood, which carries away roughly 200 to 250 mg of iron. During the initial treatment phase, sessions are usually weekly or fortnightly until the ferritin level falls into the target range of 50 to 100 micrograms per litre. Depending on how much iron has accumulated, induction can take months to a couple of years. Once the target is reached, maintenance sessions — typically every two to four months — keep the ferritin in a safe range lifelong. Through the Australian Red Cross Lifeblood therapeutic donation programme, eligible patients can have their blood used for transfusion at no cost.
Can the complications of haemochromatosis be reversed once iron is removed?

Liver fibrosis that has not yet progressed to full cirrhosis can improve substantially once iron stores are depleted — this is one of the strongest arguments for early detection and treatment. Early-stage heart muscle changes related to iron loading can also recover. Joint damage, pancreatic islet cell injury causing diabetes, and hypogonadism caused by iron-loaded pituitary or testicular tissue are unfortunately largely irreversible — the damage to these structures does not undo itself with iron removal. This is why it matters enormously to find hereditary haemochromatosis before symptoms of organ injury develop, which is exactly the goal of family cascade testing.
What foods and supplements should I avoid if I have haemochromatosis?

The single most important dietary warning is raw shellfish — oysters, mussels, and other raw seafood carry the bacterium Vibrio vulnificus, which thrives in iron-rich environments and can cause a rapidly fatal blood infection in people with iron overload. Mortality from Vibrio vulnificus in haemochromatosis exceeds 50%. Cooked seafood is safe. Iron supplements — including many men's and energy multivitamins — must be avoided because they directly add to iron stores. High-dose vitamin C supplements above 200 to 250 mg per day should be limited, as ascorbic acid enhances iron absorption and can mobilise stored iron. Alcohol should be restricted and avoided entirely in anyone with elevated ferritin or liver disease, as it greatly worsens the liver injury that iron causes.
What does cascade testing mean for my family and what will they be told?

Cascade testing means offering iron studies and HFE gene testing to every adult first-degree relative — parents, siblings, and adult children — of someone diagnosed with hereditary haemochromatosis. Because the condition is autosomal recessive, each sibling of a C282Y homozygote has a one in four chance of also carrying two copies of the gene change. Finding the condition in a relative before they develop symptoms means treatment can begin early and complications can be prevented. Before HFE genotyping is arranged, your GP will discuss what a positive result might mean for life insurance applications, because under current Australian legislation, insurers may in some circumstances ask about genetic test results.

Source quality

Sources grouped by evidence tier. AU primary tier first; international where AU is silent or lagging; named-author reconstruction where guidelines have not yet caught up. How tiers work.